3-Nitrotyrosine and related derivatives in proteins: precursors, radical intermediates and impact in function

Abstract

Oxidative post-translational modification of proteins by molecular oxygen (O2)- and nitric oxide (•NO)-derived reactive species is a usual process that occurs in mammalian tissues under both physiological and pathological conditions and can exert either regulatory or cytotoxic effects. Although the side chain of several amino acids is prone to experience oxidative modifications, tyrosine residues are one of the preferred targets of one-electron oxidants, given the ability of their phenolic side chain to undergo reversible one-electron oxidation to the relatively stable tyrosyl radical. Naturally occurring as reversible catalytic intermediates at the active site of a variety of enzymes, tyrosyl radicals can also lead to the formation of several stable oxidative products through radical–radical reactions, as is the case of 3-nitrotyrosine (NO2Tyr). The formation of NO2Tyr mainly occurs through the fast reaction between the tyrosyl radical and nitrogen dioxide (•NO2). One of the key endogenous nitrating agents is peroxynitrite (ONOO−), the product of the reaction of superoxide radical (O2•−) with •NO, but ONOO−-independent mechanisms of nitration have been also disclosed. This chemical modification notably affects the physicochemical properties of tyrosine residues and because of this, it can have a remarkable impact on protein structure and function, both in vitro and in vivo. Although low amounts of NO2Tyr are detected under basal conditions, significantly increased levels are found at pathological states related with an overproduction of reactive species, such as cardiovascular and neurodegenerative diseases, inflammation and aging. While NO2Tyr is a well-established stable oxidative stress biomarker and a good predictor of disease progression, its role as a pathogenic mediator has been laboriously defined for just a small number of nitrated proteins and awaits further studies.

Relationships among smoking, oxidative stress, inflammation, macromolecular damage, and cancer

“…Carbonylation occurs mainly in side chains of native amino acids in proteins, e.g., histidine, cysteine, and lysine, thereby giving rise to carbonyl derivatives, such as aldehyde and ketones [82,114]. The specificity of multiple amino acids to undergo carbonylation has made this modification a widely used biomarker for assessing oxidative damage to proteins [114,115]. Oxidative stress, often metal catalyzed, is a main source of protein carbonylation [116].…”

“…NO production [115,117,120]. Female mice exposed to cigarette smoke for a period of six months have shown significant increase in 3-nitrotyrosine levels in the lungs as compared to control mice exposed to clean air [121].…”

Superoxide and Non-ionotropic Signaling in Neuronal Excitotoxicity

“…While at first unclear how negating either one or the other of these reactive intermediates could prevent excitotoxic injury, the observations were reconciled by the understanding that nitric oxide and superoxide combine at an extraordinarily fast rate to form the much more toxic reactive species, peroxynitrite (ONOO − ) (Beckman et al, 1990;Radi, 2018). Peroxynitrite has subsequently become recognized as the primarily species responsible for the lipid peroxidation, DNA damage, protein nitration, and cell death that occur during excitoxicity (Lipton et al, 1994;Pacher et al, 2007;Campolo et al, 2020). Though highlighted more than 15 years ago, it remains poorly recognized how this interaction between superoxide and nitric oxide complicates the interpretation of experiments evaluating excitotoxicity, and specifically whether it is superoxide or nitric oxide that is increased (or decreased) in any particular setting (Pacher et al, 2007).…”

Oxidative-Antioxidant Imbalance and Impaired Glucose Metabolism in Schizophrenia

“…Affects the structure and function of proteins in vitro and in vivo; present in inflammation associated with vascular endothelial dysfunction and cardiovascular complications in schizophrenia [150].…”